PROJECT SUMMARY Dengue virus (DENV) is a significant threat to public health, transmitting via mosquitos and infecting hundreds of millions around the world each year, of which roughly one hundred million become symptomatic and one half-million develop severe complications such as hemorrhagic fever, shock syndrome, or death. Despite many efforts to interpret antibody and serum cytokine measurements, only once has a diagnostic test been able to differentiate patients that are susceptible to heterotypic infections that associate with greater risk for severe complications. The uncertainty of the dynamics of the immune response to DENV has repeatedly thwarted efforts to create a vaccine protecting against all prevalent serotypes for over 80 years. A perhaps even more urgent problem is the blossoming spread of chikungunya virus (CHIKV), another mosquito-borne virus characterized by higher transmissibility and infection rates much higher than those of DENV, with roughly three quarters of infected persons developing symptoms that can include chronic polyarthritis and fatigue. Sharing the same urban mosquito vectors as DENV, the transmission of CHIKV within the Western hemisphere was reported for the first time two years ago. Like DENV, there are no approved specific treatments or vaccines. So far, very little is known about the molecular interactions necessary for CHIKV to enter human cells and effectively counter the innate immune system. Next generation sequencing and immune profiling technologies such as RNA-seq, Luminex, proteomics, and CyTOF have the ability to generate a wealth of data that can be used to help illuminate global biomolecular changes driving viral infections in humans, but only if signal can be separated from noise to identify useful signatures and key pathways. The pathogenesis of an infection within a host is a complex process, involving interactions among networks of biomolecules, cell types, tissues, and host individuals. Such complexity necessitates a multiscale, integrative approach, since characterizing one network or phenomenon in isolation is unlikely to sufficiently explain changes occurring across the entire system. This study proposes analyses that will identify robust biomarkers derived from immune profiling of a longitudinal cohort of pediatric DENV and CHIKV infections in Nicaragua, as part of a multi-institutional consortium (DHIPC). Furthermore, we will integrate these data into causal network models of the host- pathogen interaction, which will reveal key driver genes for pathways that associate with changes in the host immune response and facilitate antiviral and vaccine discovery. Given the anticipated data, this proposal maximizes the impact of the modeling approach for DENV and CHIKV on future biological discovery and advances the state of the art in holistic, data-driven modeling of infectious disease.